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Isoflurane Preconditioning Induces Neuroprotection against Ischemia via Activation of P38 Mitogen-Activated Protein Kinases

Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia

A brief exposure to the volatile anesthetic isoflurane (preconditioning) induces ischemic tolerance in rat brain. However, whether isoflurane preconditioning improves long-term neurological outcome after brain ischemia and the mechanisms for this neuroprotection are not known. Here, we report that isoflurane preconditioning (2% isoflurane for 30 min at 24 h before brain ischemia) reduced brain infarct sizes and improved neurological deficit scores assessed 6, 24, and 72 h after permanent right middle cerebral arterial occlusion (MCAO) in adult male rats. More morphologically intact neurons and fewer dying cells existed in the ipsilateral frontal cortex area 1 and rostral subventricular zone of caudate putamen of isoflurane-preconditioned rats than rats undergoing MCAO alone at 14 days after the MCAO. This neuroprotection was abolished by an inhibitor of p38 mitogen-activated protein kinases (MAPK), 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580) (the percentages of infarct volumes in the ipsilateral hemisphere volumes were 34 ± 7% for MCAO, 24 ± 6% for isoflurane preconditioning plus MCAO, and 30 ± 6% for SB203580 plus isoflurane preconditioning plus MCAO, n = 8, P < 0.05 for isoflurane preconditioning plus MCAO to compare with MCAO alone or with SB203580 plus isoflurane preconditioning plus MCAO) and mimicked by an activator of these kinases, anisomycin. Isoflurane induced a rapid and prolonged increase of the phosphorylated p38 MAPK in cerebral neocortex. These active kinases distributed mainly in perikaryal regions of neurons. These results suggest that isoflurane preconditioning may improve long-term neurological outcome after focal brain ischemia and that the effects may be mediated by activating p38 MAPK.

Address correspondence to: Dr. Zhiyi Zuo, Department of Anesthesiology, University of Virginia Health System, P.O. Box 800710, One Hospital Drive, Charlottesville, VA 22908-0710. E-mail: zz3c{at}virginia.edu

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